Geron Corporation Announces Phase II Trial for Brain-Specific Anticancer Drug GNR1005

After a successful completion of a Phase I study, Geron Corporation announces the initiation of a phase II trial for its GRN1005 anticancer drug. This drug was designed to specifically treat tumors that have metastasized (spread) to the brain from the lung. This clinical trial is called GRABM-L, which stands for GRN1005 Against Brain Metastases – Lung cancer). This phase II trial is designed to determine the efficacy of GRN1005 in patients with brain metastases arising from non-small cell lung cancer (NSCLC).

GRN1005 is a novel cancer drug that consists of three molecules of the anticancer drug paclitaxel linked to a 19 amino acid peptide (Angiopep-2). This 19-amino acid peptide binds to a receptor called the “lipoprotein receptor-related protein 1” (LRP1), which is one of the most highly expressed receptors on the surface of the blood-brain barrier (BBB). Brain tumor treatment is exceedingly difficult because the central nervous system is surrounded by the BBB. The BBB prevents molecules from entering the brain unless they can bind specific receptors. When GRN1005 binds to the LRP1 receptor, the binding facilitates “receptor-mediated transport,” or transcytosis, across the BBB into the brain tissue. Conveniently, LRP1 is also very heavily expressed in many tumors. Therefore, once GRN1005 enters the brain, it can gain entry into tumor cells. GRN1005 is a “prodrug,” which means that the form that the patient takes is inactive, but the drug becomes active once it enters cells and is cleaved by enzymes called “esterases” to release active paclitaxel from the peptide.

Geron’s Executive Vice President, Head of R&D and Chief Medical Officer, Stephen M. Kelsey, M.D., said: “With the treatment of the first patient in the GRABM-L study, we have initiated both of the planned Phase 2 clinical trials of GRN1005 in patients with cancer metastases in the brain, a significant unmet medical need for which there are currently no approved drug therapies. We have been encouraged by the preliminary evidence of anti-tumor activity against brain metastases observed in the Phase 1 study of GRN1005, and we hope to confirm these results in our Phase 2 trials.”

The purpose of GRABM-L Phase 2 study is to determine the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from Non-Small Cell Lung Cancer. The trial plans to enroll 50 patients, who will receive one intravenous dose of GRN1005 every three weeks (650 mg/m2). The primary efficacy endpoint for the trial is the response of the tumors to the drug during the course of treatment.

Patients with brain cancer, particularly secondary tumors that are the result of metastases, currently have few options. The reason for this treatment dead-end is the difficulty in getting antitumor drugs to effectively cross the blood-brain barrier and enter the tumor. Preclinical and Phase 1 data indicate that GRN1005 not only transports paclitaxel into tumors inside the brain through LRP1-mediated transport, but also has activity against tumors outside the brain.

Data on safety and tolerability, and preliminary evidence of anti-tumor activity of GRN1005 were documented in two separate Phase 1 multi-center, open-label, dose escalation clinical trials, conducted by Angiochem, Inc. In these trials, patients with heavily pre-treated progressing, advance-stage solid tumors and brain metastases (n=56; including NSCLC) and patients with recurrent or progressive malignant glioma (n=63) were treated with GRN1005. Final data were presented at the 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November. The data were encouraging. In patients with brain metastases from solid tumors, overall response rate was 20% (4/20) by one-dimensional assessment when treated with a dose of 650 mg/m2 of GRN1005 administered as single-agent therapy once every three weeks. Anti-tumor activity was observed against metastases inside the brain and in organs outside the brain, such as the liver, lung and lymph nodes.

Geron’s clinical development plan for GRN1005 includes two Phase 2 clinical trials in patients with brain metastases arising from either breast cancer (GRABM-B) or non-small cell lung cancer (GRABM-L). Top-line data from both studies are expected to be available by the end of the second quarter of 2013.